The role of metabolism in carbon tetrachloride-mediated immunosuppression: in vivo studies.
The role of metabolic bioactivation for carbon tetrachloride-mediated suppression of humoral responses was investigated in B6C3F1 mice. Subchronic studies with CCl4 demonstrated that this chlorinated hydrocarbon markedly suppressed T-dependent antibody responses following 7 consecutive days of administration at doses between 500 and 5000 mg/kg. No significant difference in the magnitude of suppression was observed between the ip and oral routes of exposure. Thirty-day ip administration of CCl4 at doses as low as 25 mg/kg also resulted in a significant inhibition of T-dependent antibody responses. The results from both the 7-day and the 30-day studies indicate that a greater than 50% suppression of antibody responses could not be achieved even at doses of CCl4 as high as 5000 mg/kg. In vivo studies utilized the cytochrome P450 competitive inhibitor, aminoacetonitrile (AAN), in an effort to block the effects of exposure to CCl4. Both the hepatotoxicity, as measured by serum glutamic pyruvic transaminase levels, and the suppression of the T-dependent antibody response to sRBC were reversed by treatment with AAN. Conversely, induction of cytochrome P450, by pretreatment of mice with ethanol prior to treatment with CCl4, resulted in the potentiation of the immunosuppressive effects of CCl4. AAN and ethanol administered alone had no effect on antibody responses. In order to assess the effect of CCl4 treatment on cytochrome P450 activity at doses which cause immunosuppression, measurements of total microsomal protein and specific substrate activities were determined. Significant decreases were observed in both total hepatic microsomal protein as well as in aminopyrine N-demethylase activity, aniline hydroxylase activity, and aryl hydrocarbon hydroxylase activity following treatment with CCl4 for 7 days at doses ranging from 5 to 1000 mg/kg. All of the cytochrome P450 parameters that were measured, following CCl4 treatment, demonstrated very flat dose-response curves which appeared to parallel the effects of CCl4 on antibody responses.
Kaminski
N E
NE
Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298.
Barnes
D W
DW
Jordan
S D
SD
Holsapple
M P
MP
D000607:Aminoacetonitrile / Q000494:pharmacology; D000818:Animals; D000921:Antibody-Producing Cells / Q000187:drug effects / Q000276:immunology; D001711:Biotransformation / Q000187:drug effects / Q000502:physiology; D002251:Carbon Tetrachloride / Q000493:pharmacokinetics* / Q000633:toxicity; D002252:Carbon Tetrachloride Poisoning / Q000276:immunology / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects* / Q000502:physiology; D007114:Immunization / Q000379:methods; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D013154:Spleen / Q000187:drug effects / Q000276:immunology
D000607:Aminoacetonitrile; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride